Inflammatory bowel diseases, interleukin-6 and interleukin-6 receptor subunit alpha in causal association with cerebral cortical structure: a Mendelian randomization analysis

Chunlong Liu; Shijie Zhu; Jian Zhang; Kuiwu Ren; Kangkang Li; Jiangtao Yu

doi:10.3389/fimmu.2023.1154746

Inflammatory bowel diseases, interleukin-6 and interleukin-6 receptor subunit alpha in causal association with cerebral cortical structure: a Mendelian randomization analysis

Front Immunol. 2023 Apr 20:14:1154746. doi: 10.3389/fimmu.2023.1154746. eCollection 2023.

Authors

Chunlong Liu¹, Shijie Zhu², Jian Zhang³, Kuiwu Ren¹, Kangkang Li⁴, Jiangtao Yu^{1

4}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, Fuyang People's Hospital, Anhui Medical University, Fuyang, China.
² Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, China.
³ Department of Neurosurgery, The Seventh Clinical College of China Medical University, Fushun, China.
⁴ Department of Hepatobiliary and Pancreatic Surgery, Fuyang People's Hospital, Bengbu Medical College, Fuyang, China.

Abstract

Background: Neurological involvement and psychiatric manifestations have been documented in clinical cases of inflammatory bowel disease (IBD); however, the presence of a causal relationship remains elusive. The objective of this study is to investigate the modifications occurring in the cerebral cortex as a result of IBD.

Methods: A compendium of data extracted from a genome-wide association study (GWAS) involving a maximum of 133,380 European subjects. A series of Mendelian random analyses were applied to exclude heterogeneity and pleiotropy, ensuring the stability of the results.

Results: Neither IBDs nor inflammatory cytokines (IL-6/IL-6Rα) were found to have a significant causality with surface area (SA) and thickness (TH) at the global level. At the regional functional brain level, Crohn's disease (CD) significantly decreased the TH of pars orbitalis (β=-0.003mm, Se=0.001mm, p_ivw =4.85×10^-4). IL-6 was observed to reduce the SA of middle temporal (β=-28.575mm², Se=6.482mm², p_ivw=1.04×10^-5) and increase the TH of fusiform (β=0.008mm, Se=0.002mm, p_ivw=8.86×10^-5) and pars opercularis (β=0.009mm, Se=0.002mm, p_ivw=2.34×10^-4). Furthermore, a causal relationship between IL-6Rα and an increase in the SA of superior frontal (β=21.132mm², Se=5.806mm², p_ivw=2.73×10^-4) and the TH of supramarginal (β=0.003mm, Se=0.0002mm, p_ivw=7.86×10^-37). All results passed sensitivity analysis and no heterogeneity and pleiotropy were detected.

Conclusion: The correlation between IBD and changes in cerebral cortical structures implies the existence of a gut-brain axis at the organismal level. It is recommended that clinical patients with IBD prioritize long-term management of inflammation, as changes at the organismal level can lead to functional pathologies. Magnetic resonance imaging (MRI) may be considered as an additional screening option for IBD.

Keywords: Crohn’s disease; IL-6; IL-6Rα; Mendelian randomization; brain cortical structure; inflammatory bowel disease; ulcerative colitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cerebral Cortex / metabolism
Genome-Wide Association Study
Humans
Inflammatory Bowel Diseases* / genetics
Interleukin-6* / genetics
Interleukin-6* / metabolism
Mendelian Randomization Analysis
Receptors, Interleukin-6* / genetics

Substances

Interleukin-6
Receptors, Interleukin-6
IL6 protein, human
IL6R protein, human

Grants and funding

This study was supported by grants from the Special project for translation of clinical medicine in Anhui Province (202204295107020054) and scientific research project of Fuyang Health and Health Commission(2021xkj088).